The objective of this proposal is to finalize development of CLT-005, a novel small molecule inhibitor of Stat3, through the performance of studies required for the submission of an investigative new drug application with the US Food and Drug Administration (FDA). Activation of the Stat3 pathway in retinal inflammatory and angiogenic diseases has been observed in both clinical and basic science studies. We have demonstrated that CLT-005 prevents Stat3-induced cellular changes in an animal model of diabetes. Following intravitreal administration, CLT-005 reduces retinal vascular permeability, and the expression of numerous angiogenic and inflammatory genes and proteins. Additionally, both CLT-005 and the PEG-based depot-forming formulation were well tolerated following intravitreal injection, had no effect on visual physiology, and produced a favorable in-vitro safety profile. The goal of this proposal is to: 1) Produce GMP amounts of CLT-005 sufficient for toxicity studies and human clinical trials; 2) Perform formulation of CLT-005 into sterile fill vials and conduct stability studies; 3) Complete preparation of the CMC section for the IND application; 4) Perform pharmacokinetic studies of formulated and unformulated CLT-005; 5) Perform ocular distribution studies of formulated CLT-005; 5) Conduct single and multiple dose GLP toxicology and toxicokinetic studies; 6) Perform genetic toxicology studies; and 7) Perform in-vitro cardiac safety pharmacology studies. These studies are mandated by the FDA in order to receive approval for the initiation of human clinical trials. For ocular drug development, the FDA also requires that toxicology studies be performed in two large eye animal models, such as monkeys and rabbits, which will be utilized for completion of the experiments outlined above. As CLT-005 has a profound effect on reducing retinal vascular leakage we intend to seek an indication for treating Diabetic Macular Edema, a disease that currently has no FDA-approved pharmaceutical therapy. We believe that CLT- 005 will also be efficacious in patients suffering from Age-Related Macular Degeneration (AMD) and Diabetic Retinopathy (DR). Following the successful completion of Phase II human clinical studies of CLT-005, we intend to file new IND applications to investigate the use of CLT-005 in treating AMD and DR. CLT-005 could also prove to be an effective combinatorial therapy with existing anti-VEGF treatments to reduce the frequency of clinical dosing. PUBLIC HEALTH RELEVANCE: Retinal vascular leakage, inflammation, or breakdown of the blood-retina barrier are pathogenic features of Diabetic Macular Edema (DME) and cause a subsequent loss of vision. Currently, there are no FDA-approved drug treatments for DME. In this Phase II project, we will finalize studies of CLT-005, a novel small molecule therapeutic, to enable the submission of an investigative new drug application to the FDA. These studies include preparation of sterile materials and formulations, performance of pharmacokinetic studies, and performance of rigorous toxicology/safety studies that are mandated by the FDA and essential for human clinical trials. Although we intend to seek an initial indication for DME, it is likely that CLT-005 will also confer a significant therapeutic benefit to patients suffering from Diabetic Retinopathy and Age-Related Macular Degeneration.